S282: ERYTHROPOIESIS INDUCTION THROUGH BONE MARROW TFR2 DELETION REDUCES BLOOD GLUCOSE LEVELS IN WILD-TYPE AND Β-THALASSEMIC MICE
Authors: Simona Maria DI Modica, Celia Cordero-Sanchez, Mariateresa Pettinato, Alessia Pagani, Laura Silvestri, Antonella Nai
Journal: HemaSphere (2023)

Background: Β-Thalassemia is a genetic disease due to mutations in the β-globin gene characterized by anemia, ineffective erythropoiesis (IE), splenomegaly and iron-overload. Glucose intolerance and diabetes are common complications, usually ascribed to iron toxicity and tissue damage. However, β-thalassemia carries, who do not experience iron overload, have a risk of developing glucose abnormalities higher than the general population. Thus, other factors are likely involved in diabetes pathogenesis and progression. Transferrin receptor 2 (TFR2) is a player of the iron-erythropoiesis cross-talk. In the liver it contributes to the transcriptional activation of hepcidin, the master regulator of systemic iron metabolism, while in erythroid cells it negatively modulates erythropoietin signaling. Tfr2 inactivation in bone marrow (BM) cells stimulates erythropoiesis in wild-type (wt) mice and ameliorates anemia and iron overload in β-thalassemia models, likely increasing the metabolic activity of erythroid cells. Aims: Since mice with massive erythropoiesis expansion due to JAK2 mutations show a similar rearrangement of erythroid energetic metabolism leading to systemic hypoglycemia, we aim at verifying whether BM Tfr2 deletion might prevent the metabolic alterations of β-thalassemia mouse. Methods: Wt and thalassemic mice with (Tfr2BMWT and Hbbth3/+) or without BM Tfr2 (Tfr2BMKO and Tfr2BMKO/Hbbth3/+) were generated through BM transplantation (BMT). Complete blood count, fasting and non-fasting glycemia, serum insulin levels, response to glucose (GTT) and insulin (ITT) tolerance test and muscularity were evaluated 8-11 weeks after BMT. Results: As expected, Hbbth3/+ mice showed severe anemia, while Tfr2BMKO and Tfr2BMKO/Hbbth3/+ animals had higher red blood cell (RBC) count and hemoglobin (Hb) levels than Tfr2BMWT and Hbbth3/+ controls respectively, confirming that hematopoietic Tfr2 deletion enhances erythropoiesis. In line with patients’ data, Hbbth3/+ mice were hyperglycemic both in basal conditions and after 16 hours of starvation. Interestingly, Tfr2BMKO mice showed reduced non-fasting glycemia as compared to Tfr2BMWT, while Tfr2BMKO/Hbbth3/+ animals had lower fasting and non-fasting blood glucose levels than Hbbth3/+ in the absence of changes in circulating insulin, suggesting that hematopoietic Tfr2 deletion reduces glycemia in both a wt and thalassemic context, likely increasing glucose consumption by the enhanced erythropoiesis. In agreement, blood glycemia negatively correlated with both RBC count and Hb levels, again supporting the hypothesis that alterations in erythropoiesis might significantly impact systemic glucose metabolism. Hbbth3/+ mice, but not Tfr2BMKO/Hbbth3/+, were more sensitive to glucose administration than Tfr2BMWT in a GTT. However, animals of the 4 genotypes responded similarly to ITT, suggesting that, at this time point, the hyperglycemia of Hbbth3/+ mice was not due to reduced insulin sensitivity. Finally, Hbbth3/+ mice showed reduced muscular strength as compared to Tfr2BMWT, rescued by BM Tfr2 deletion. Summary/Conclusion: Overall our data, in agreement with previous transcriptomic analyses, suggest that early metabolic alterations of β-thalassemia mice are strictly dependent on the degree of IE and might be prevented by BM Tfr2 deletion, that likely increases glucose utilization to sustain the augmented erythropoiesis in an insulin-independent manner. This effect is evident also in a non-thalassemic context, suggesting that enhancing erythropoiesis through hematopoietic TFR2 targeting might become a novel general strategy for the control of blood glucose levels. Keywords: Erythropoieisis, beta thalassemia, Transferrin receptor